What are the key developments in pharmaceutical manufacturing? From large-scale biomanufacturing projects, to advances in cell and gene therapy production, and continuous manufacturing, DCAT Value Chain Insights looks at significant investments and technical gains.

A Top 10 listing of key manufacturing developments

1. Large-scale biomanufacturing projects: Bristol-Myers Squibb. Bristol-Myers Squibb is among the large pharmaceutical companies proceeding with a large-scale biomanufacturing project. Its key project is in Ireland following the company’s $750-million investment for a new biologics bulk manufacturing facility in Devens, Massachusetts. Bristol-Myers Squibb’s plan to open a new EUR 900 million ($1.02 billion) large-scale biologics manufacturing facility in Cruiserath, County Dublin, near Blanchardstown that will produce multiple therapies for the company’s growing immuno-oncology portfolio. The manufacturing facility is estimated to be operational in 2019.

The new facility follows another large-scale biomanufacturing investment by the company. In 2016, Bristol-Myers Squibb completed a major expansion at its Devens facility. The $280-million project added two new buildings to the 89-acre Devens campus: a biologics development building for designing processes for the early production of investigational medicines, and a clinical manufacturing building where investigational medicines will be produced to support clinical trials. Both are new capabilities for Devens, a site that had previously focused solely on large-scale, bulk biologics manufacturing. The two new buildings also add approximately 200,000 square feet to a site now comprised of eight major buildings in a 600,000-square-foot complex. When combined with the company’s initial $750 million investment to build the facility, the expansion project brings the company’s total investment at the site to more than $1 billion.

2. Large-scale biomanufacturing projects: Boehringer Ingelheim. Boeheringer Ingelheim is another company advancing biomanufacturing projects. In December 2015, Boehringer Ingelheim announced an approximate EUR 500 million ($568 million) investment for a new large-scale biopharmaceutical production facility for active ingredients manufactured using cell cultures at its site in Vienna, Austria. In Vienna, Boehringer Ingelheim has up to its announcement produced active ingredients using microorganisms; over the next few years, cell-culture technology will also be transferred there. The new production plant is scheduled be operational by 2021. The company already has two large-scale facilities in Biberach, Germany used for market launch and cell-culture-based manufacture of biopharmaceuticals. Biberach will remain Boehringer Ingelheim’s largest European cell culture and global launch site for biopharmaceutical products.

Earlier this year (June 2018), Boehringer Ingelheim announced plans to invest EUR 230 million ($267 million) in a new biologicals development center (BDC) at the company’s research and development (R&D) site in Biberach, Germany. The center will integrate biologicals analytical and process development as well as manufacturing for clinical studies into one unit while at the same time increasing development capacity. Following a staggered launch beginning in 2020, the new building will house 500 employees. The move follows recent investments to further increase BI’s mammalian cell-culture capabilities, including the large-scale biopharmaceuticals facility in Vienna, Austria, a new biopharmaceuticals facility in Shanghai, China, and the expansion of existing large-scale biopharmaceutical capacities in Fremont, California.

3. Investment in US pharmaceutical manufacturing. Several large pharmaceutical companies have announced manufacturing investments in the US in part due to US tax reform, which reduced the US corporate tax rate. Earlier this year (July 2018), Pfizer announced plans to invest $465 million to build a sterile injectable pharmaceutical production facility in Portage, Michigan. The new 400,000-square-foot production facility will expand Pfizer’s presence in Portage, where the company employs more than 2,200 people at one of its largest plants. The investment is part of an overall plan announced by the company in January 2018 to invest approximately $5 billion in US-based capital projects as a result of the enactment of US tax reform. During the next six years, the company expects to invest approximately $1.1 billion in Kalamazoo County in Michigan—which is in addition to the $1 billion it has invested in the site over the past decade.

Also, earlier this year (July 2018), Amgen broke ground for a new biomanufacturing plant that will be constructed at its West Greenwich, Rhode Island campus. The new plant, worth up to $200 million, will manufacture products for the US and global markets. In January 2018, Amgen announced a five-year capital investment plan of $3.5 billion, which included committing up to $300-million to build a new manufacturing plant in the US, in part encouraged by US tax reform.

In 2017, Eli Lilly and Company announced plans to invest $72 million in an insulin-manufacturing project at one of its facilities in Indianapolis, Indiana. The project is part of the company’s $850-million investment in US capital projects, which Lilly announced in March 2017.

4. Manufacturing cell therapies. New modalities create the need for manufacturing capacity and technology and such is the case with cell therapies with Novartis, Gilead Sciences, and Celgene among the companies advancing cell-therapy manufacturing projects. Novartis received FDA approval of Kymriah (tisagenlecleucel), a chimeric antigen receptor (CAR) T-cell therapy, in 2017, the first CAR-T cell therapy approved by the FDA. It received European approval last month (August 2018). Novartis has been actively pursuing options to expand manufacturing capabilities for cell therapies beyond its facility in Morris Plains, New Jersey. This includes an agreement with CELLforCURE, based in France and one of the first and largest contract development and manufacturing organizations (CDMOs) producing cell and gene therapies in Europe, an expanded alliance with the Fraunhofer Institute, which currently supports the manufacturing of Kymriah for global clinical trials and for post approval manufacturing, as well as technology transfer efforts to a CDMO in Japan.

Gilead Sciences, which acquired Kite Pharma, a cell and gene therapy company for $11.9 billion in 2017, announced earlier this year, that it has leased and purchased new facilities in the US and Europe to expand its cell-therapy manufacturing capabilities. Kite has leased a new 117,000-square-foot site facility in Hoofddorp, the Netherlands to engineer cell therapies. The facility will engineer and produce cell therapies, including axicabtagene ciloleucel, a CAR T cell therapy that was approved by the European Medicines Agency in August 2018 and which was approved in October 2017 in the US as Yescarta for treating adult patients with relapsed or refractory large B-cell lymphoma. The new facility is scheduled to be fully operational in 2020. In addition to the Netherlands facility, Kite has recently purchased a new building in Santa Monica from Astellas Pharma that will be used for cell-therapy research, development, and the expansion of clinical manufacturing capabilities. Kite has also leased a 26,000-square-foot facility in Gaithersburg, Maryland. The Maryland site will support the work of a new Cooperative Research and Development Agreement with the National Cancer Institute to develop adoptive cell therapies targeting patient-specific tumor neoantigens. Neoantigens are mutations found on the surface of cancer cells that are unique to each person and tumor.

Celgene, which acquired Juno Therapeutics, a company developing cell therapies and immunotherapies, earlier this year for $9 billion, announced in February 2018 that it completed the first phase of a new immunotherapy manufacturing center for CAR-T therapies at its Summit West campus in New Jersey. Celgene is involved in cellular therapy development through its Celgene Cellular Therapeutics business that focuses on placenta-derived and other stem-cell therapies in multiple diseases.

5. Manufacturing low-volume drugs. When new drugs come to market, there are manufacturing issues as well, so a review of trends in approvals of new molecular entities (NMEs) can provide insight into manufacturing activity. A key trend in NME approvals over the past several years is the increased share of orphan drugs approved as NMEs. Orphan drugs are defined as drugs that treat diseases that affect 200,000 or fewer people, as defined by the US Food and Drug Administration (FDA), which provides incentives, including market-exclusivity benefits, for developing orphan drugs. With a smaller patient population, these drugs are typically produced in lower volumes than primary care drugs. Orphan drugs have accounted for approximately 40% of NME approvals by the FDA over the past several years. In 2017, the FDA’s Center for Drug Evaluation and Research approved 18 NMEs that were orphan drugs, representing 39% of the 46 NMEs approved. In 2016, 9 of the 22 the NMEs approved by the FDA were orphan drugs. Of these 22 new molecular entity approvals, two were diagnostic agents, so 9, or 45%, of the new drugs approved in 2016 were orphan drugs. In 2015, 21, or 47%, of the 45 NMEs approved by the FDA were orphan drugs and in 2014, 17 of the 41 NMEs approved were orphan drugs, representing 41% of NME approvals that year. 

6. High-potency manufacturing. Oncology is the largest therapeutic sector in the global and US pharmaceutical markets, which creates the need for specialized manufacturing capabilities for both drug substances and drug products. Global spending on cancer therapies and supportive-care products rose to $133 billion globally in 2017, up from $96 billion in 2013, and US spending on cancer drugs reached almost $50 billion in 2017, according to a recent analysis, Global Oncology Trends 2018: Innovation, Expansion and Disruption, by the IQVIA Institute for Human Data Science. On a pipeline basis, the industry’s pipeline for oncology drugs reached an historic level of 710 molecules in late-stage development in 2017, up more than 60% from a decade ago, and with almost 90% of the therapies being targeted treatments, according to the IQVIA report. Of the 710 molecules in late-stage development, 335, or 47% are small molecules, and 301, or 45% are biologics. The remaining types are: cytotoxics (54 molecules, or 8% of the industry’s pipeline); hormonals (17 molecules, or 2% of the pipeline); and radiotherapies (three molecules, or 0.4% of the pipeline). Biologics, including newer approaches, such as immunotherapies, constitute the oncology-drug market, but small molecules, including cytotoxics, and hybrid approaches, such as antibody-drug conjugates (ADCs) are also part of the market and create need for high-potency or high-containment manufacturing.

7. Small-molecule manufacturing shifts. As pharmaceutical companies increase product development into biologics, they are also re-aligning their supply networks. A case in point is Bristol-Myers Squibb. In addition to its investments in large-scale biomanufacturing as previously outlined, the company made some moves to rationalize its small-molecule supply network. Earlier this year (January 2018), the company completed the sale of its small-molecule active pharmaceutical ingredient manufacturing facility in Swords, Ireland, to SK Biotek, a wholly-owned subsidiary of SK Holdings, based in Seoul, South Korea. SK Biotek is operating the plant as a stand-alone CDMO and intends to add marketing, research and development talent, and invest in upgrades to bring additional capacity to the site. The sale of the facility was part of a larger decision, announced in 2016, in which Bristol-Myers Squibb said it will evolve its manufacturing network in alignment with its product focus and priorities. The company said that approximately 75% of its developmental pipeline is in biologics and that the company will continue to invest in biologics manufacturing and streamline small-molecule operations. The company pointed to its two large-scale biologics manufacturing investments in the US and Europe.

8. Reduction of opioids by cutting production. The opioid crisis in the US has engendered a number of policy proposals and actions to curb the problem, including production of these drugs. Last month (August 2018), the US Department of Justice and the US Drug Enforcement Administration (DEA) proposed a reduction for controlled substances that may be manufactured in the US in 2019. The proposal decreases manufacturing quotas for six opioids for 2019 by an average of 10% as compared to the 2018 amount. The DEA has proposed to reduce the more commonly prescribed Schedule II opioids, including oxycodone, hydrocodone, oxymorphone, hydromorphone, morphine, and fentanyl. The DEA says the move to cut opioid product is part of President Donald Trump’s Safe Prescribing Plan that seeks to cut nationwide opioid prescription fills by one-third within three years. The DEA said the quotas apply to the six most frequently misused opioids.

9. Risk-based manufacturing inspections. The FDA is continuing its plan to use a risk-based selection model for manufacturing inspections, which is part of its strategy to allocate resources more effectively and gain greater parity between inspections of domestic and foreign drug-manufacturing facilities. Earlier this month (September 2018), the FDA published an internal policy that outlines the agency’s risk-based, site-selection model for inspecting foreign drug-manufacturing facilities. As of fiscal year 2017, there were about 5,063 human pharmaceutical sites worldwide subject to routine surveillance inspection with 3,025 of those foreign-based, according to information from the FDA. For that year, the FDA conducted 1,453 drug surveillance inspections, including 762 of foreign sites. The FDA prioritizes inspections of sites regardless of their location, by using a risk-based site-selection model. For manufacturing facilities in other countries, inspections may be conducted by staff in foreign offices, those on temporary duty assignments, or staff that travel internationally to conduct the inspection. In addition, the FDA pursues opportunities to collaborate with other countries.

10. Advancing continuous manufacturing. The FDA continues to support the advancement of continuous manufacturing. Earlier this year, it awarded a total of $6 million to three universities (Rutgers University, The Massachusetts Institute of Technology and the Georgia Institute of Technology) to study and recommend improvements for continuous manufacturing for drug substances and drug products. The FDA made the awards under its authorization from the 21st Century Cures Act, which was signed into law in 2016 and is designed to help accelerate medical product development. Its authorization allows grants to institutions of higher education and non-profit organizations to study and recommend improvements for the continuous manufacturing of drugs and biological products as well as similar innovative monitoring and control techniques. The FDA has been increasing its support of new technology, such as continuous manufacturing, by helping industry learn how to implement them. The FDA established its Emerging Technology Program in 2017 to help industry implement innovative technologies to improve product quality and modernize the industry. Under this program, the FDA engages with industry early in their process of developing new technology and discusses and helps resolve any anticipated regulatory or scientific issues prior to the submission of product applications. The agency says many companies have applied to the Emerging Technology Program regarding continuous manufacturing, which has enabled the FDA to quickly review and approve applications involving continuous manufacturing operations.